Human papillomaviruses (HPVs) are etiologically associated with 5% of human cancers including most anogenital cancers of the cervix, vagina, vulva, penis and anus, as well as a growing subset of head and neck cancers, particularly of the oropharynx. During the current funding period, genome-wide analyses of a large panel of human cervical tissues from women with different stages of neoplastic disease from normal to low grade CIN to high grade C1N3 to cancer have identified multiple cellular genes and pathways dysregulated at specific times in this progressive disease. One of these is the estrogen/estrogen receptor a (ERa) signaling pathway. During this same period mouse model studies led to the discovery that ERa expression in the stroma is essential for cervical neoplastic disease in the epithelium. Proposed are studies using the genome-wide analyses of neoplasia-associated stroma in women and genetically engineered mouse models altered in expression of specific paracrine factors and their receptors to define the signals elicited from the stroma that are contributing to stromal ERa-mediated effects on cervical carcinogenesis. Another example of integrating the knowledge gained from genome wide analyses with mouse model studies regards a second gene of interest, ATAD2, which is upregulated in the human cervical cancer and precursor lesions, and in HPV-16 E7 transgenic mice. ATAD2 is an E2F-induced transcriptional co-activator of c-Myc, representing a link between the E2F and Myc pathways, both important in cancer. ATAD2's role in cervical cancer will be studied using mouse models. The third direction of this project is dnven by a new mouse model for studying the role of cutaneous HPVs in skin cancer. While HPVs role in skin cancer in the general population remains highly debated, it has a well-documented role in causing skin cancer in patients with the disease Epidermodysplasia Verruciformis (EV), caused by homozygous mutations in one of two genes, EVER1 and EVER2. Project 1 has now established a mouse model for EV, using mice nulligenic for EVER1 or EVER2, with which to test alternative hypotheses for why EV patients are at risk for HPV-induced skin cancers.